A meta-analysis of Chinese herbal medicine in treatment of managed withdrawal from heroin

Liu TT, Shi J, Epstein DH, Bao YP, Lu L

CRD summary

The review compared efficacy and safety of Chinese herbal medicine with western medicine on managed withdrawal from heroin and concluded that Chinese herbal medicine was more effective and had a better safety profile than alpha2 adrenergic agonists, but not opioid agonists. Given major shortcomings in the review process and interpretation of results, the reliability of the conclusions is unclear.

Authors' objectives

To assess the efficacy and safety of Chinese herbal medicine on heroin detoxification during the first 10 days of withdrawal

Searching

EMBASE, PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) and four Chinese databases (Chinese Biomedical Database, China National Knowledge Infrastructure, Wanfang and VIP database) were searched for relevant studies published from January 1990 to August 2007. Search terms were reported. Reference lists from retrieved articles were searched. Contacts made with experts in the field to find ongoing and unpublished studies.

Study selection

Eligible studies were randomised controlled trials (RCTs) (with at least 15 participants in each group) that compared Chinese herbal medicine with western medication (alpha2-adrenergic agonists or opioid receptor agonists) for heroin detoxification in patients diagnosed with heroin or opioid dependence in the acute stage of abstinence symptoms. Studies needed to provide demographic and drug use information for included patients and data on either total score on the opioid-withdrawal symptoms scale (WSS), anxiety score (Hamilton Anxiety Scale, HAMA) or rate of adverse effects. Studies were excluded if Chinese herbal medicine was given in combination with other medications or for particular low quality features or evidence of heterogeneity.

Participants in the included studies ranged in age from 23 to 39 years, were mostly male and had been using heroin daily from seven to 94 months, mostly by intravenous injection or insufflation. Chinese herbal medicine included 18 herb formulas. The most frequently used herbs were Radix Ginseng, Rhizoma Corydalis, Radix Aconiti Lateralis Preparata, Radix Glycyrrhizae, Flos Daturae and Radix Angelicae Sinensis. Comparison medications included alpha2-adrenergic agonists (clonidine or lofexidine), opioid agonists (methadone or buprenorphine) or both (clonidine and methadone). All included studies were undertaken in China.

Two reviewers assessed the studies for inclusion in the review by reading titles and abstracts. Disagreements were resolved by consensus.

Assessment of study quality

Methodological quality of included studies was assessed using the Jadad scale (Jadad 1996) for randomisation method, double blinding, description of withdrawal, description of randomisation and description of blinding (maximum 5 points). Trials that scored 2 or fewer points were regarded as poor quality and 3 or greater points as high quality.

The authors did not state how many reviewers performed quality assessment.

Data extraction

Descriptive study data and demographic characteristics of participants were extracted. WSS outcomes were extracted separately for days 0 (before treatment) to 10 (after treatment). HAMA outcomes were extracted separately for day 0 (before treatment), day five (during treatment) and day 10 (after treatment). Rates of specific adverse effects were extracted.

The authors did not state how many reviewers performed data extraction.

Methods of synthesis

Pooled weighted mean difference (WMD), with 95% confidence intervals (CI), between comparison groups was calculated for continuous outcomes and relative risk (RR), with 95% CI, was calculated for dichotomous outcomes. Fixed-effects models were used when there was no significant heterogeneity and, otherwise, random-effects models were used. Heterogeneity was considered significant when 95% CIs did not overlap. Pooled analysis was stratified by the two most common control interventions, alpha2-adrenergic agonists or opioid-receptor agonists. Sensitivity analysis was carried out to assess the effect of study quality on effect estimates and to estimate fail-safe numbers of negative studies that could overturn the results.

Results of the review

Twenty-one RCTs (n=2,949 participants) were included. Ten RCTs were assessed as high quality (Jadad score between 3 and 5 points). Heterogeneity was not formally assessed. Estimation of fail-safe numbers of negative trials indicated that publication bias was unlikely to have influenced the results, where differences were reported as significant.

WSS: Chinese herbal medicine was superior to alpha2-adrenergic agonists for days four to seven and days nine to 10; there were no significant differences in treatments for all the other days (nine high-quality studies). Chinese herbal medicine was inferior to opioid receptor agonists for days one to three; results favoured Chinese herbal medicine on days seven and 10; there were no significant differences between treatments for all other days (seven studies).

HAMA: Chinese herbal medicine was superior to alpa2-adrenergic agonists in relieving anxiety at end of treatment (day 10) (WMD -0.48, 95% CI -0.8 to -0.2; seven studies). There was no evidence of a significant difference on day five (six studies) or when Chinese herbal medicine was compared with opioid receptor agonists at any time point (one study).

Adverse events: Chinese herbal medicine was less likely to be associated with fatigue (RR 0.36, 95% CI 0.21 to 0.61; five studies) or dizziness (RR 0.49, 95% CI 0.34 to 0.7; eight studies) than alpha2 adrenergic agonists. There was no evidence of a difference in the other adverse effects studied: blurred vision (seven studies); somnolence (four studies); and dry mouth (eight studies).

Chinese herbal medicine was not as effective as opioid agonists but was more effective than alpha2 adrenergic agonists in relieving managed symptom withdrawal from heroin and may have relieved anxiety with fewer side effects. More research was required to determine the specific forms of Chinese herbal medicine that were effective and types of patients who could be helped.

CRD commentary

The review had clearly stated inclusion criteria with respect to study design, participants, interventions and outcomes. This seemed appropriate, but the broad definition of Chinese herbal medicine presented difficulties in interpreting which components might be effective. A range of searching methods were employed and these included attempts to find unpublished studies. Formal assessment of publication bias with estimation of fail-safe numbers of negative studies indicated that publication bias was unlikely. It was not stated whether language restriction was applied and so language bias could not be ruled out. Study quality was assessed appropriately, but there were some omissions in reporting how this was undertaken and how data extraction was performed. Sensitivity analysis was performed to assess how study quality influenced the results and differences were reported. The authors provided sufficient detail about individual studies; however, there were difficulties in interpretation of the results, given that some overall results were reported with restrictions only to the high-quality studies (CMH compared to alpha2 adrenergic agonists) and other overall results included all studies regardless of quality. Follow-up for assessment of outcomes was only 10 days, so it was unclear whether the effects reported were sustained. Heterogeneity was not formally assessed and likely to be substantial, given the broad definition of Chinese herbal medicine. Analyses at multiple time points during the 10-day observation period was likely to be associated with spurious results and the authors did not appear to have adjusted for this. Although the review was restricted to RCTs and half were assessed as high quality, concerns about the review process and interpretation of the resultsmade the reliability of the conclusions unclear.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that future trials should assess influence of specific forms of Chinese herbal medicine on outcomes, influence of duration and severity of heroin dependence on outcomes, types of patients who might benefit and influence on relapse prevention as well as detoxification.

Funding

National Basic Research Program of China (973 Program, 2003CB515400), National High Technology Research and Development Program of China (863 Program, 2006AA02Z4D1), China-Canada Joint Health Research Program (No: 30611120528).

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.